This article provides an overview of emerging directions in the materials science of biointegrated electronic and microfluidic systems, as defined by technologies that are capable of supporting long-term, intimate, physical interfaces to living organisms. Here, deterministic hard/soft composite structures, including those that leverage concepts in fractal mathematics, serve as the materials foundations for diverse devices of this type. Examples of “epidermal” or skin-like electronic systems for biophysical tracking of patient conditions that range from stroke to hydrocephalus illustrate the engineering maturity and operational sophistication that is now possible. Recent ideas in soft, skin-mounted, microfluidic lab-on-a-chip systems extend the capabilities of such platforms to include biochemical assessments of physiological status via capture, storage, manipulation, and in situ detection of biomarkers in microliter volumes of sweat, collected as it emerges from the surface of the skin. The article concludes with a description of mechanically guided assembly schemes that provide access to three-dimensional, open-mesh constructs, as a frontier area of materials development in this broader area of biointegrated systems.